The data indicate selective effects of JDTic on different aspects of EtOH self-administration behavior. A single injection of JDTic (all doses tested) 14 days prior to testing reduced the expression of EtOH-seeking in P rats, as measured in the PSR test. Additionally, the same single injection of JDTic (given 25 days before) suppressed responding on the EtOH lever under relapse conditions. To our knowledge, this is the first example of JDTic demonstrating a long-lasting effect on EtOH-seeking or EtOH relapse behavior. Previous research demonstrated that JDTic is pharmacologically active for greater than 21 days following a single subcutaneous injection (Beardsley et al., 2005
) and up to 28 days following intra-gastric administration (Caroll et al., 2004). However, for the current research, it is uncertain whether the single administration of JDTic reduced EtOH-seeking and EtOH relapse behavior by preventing the development of the biological basis of these two phenomena, reducing the expression of these behaviors through a reduction in lever responding, or a combination of the two (development/expression). Given that JDTic did not significantly decrease operant responding on the water lever during both PSR and relapse testing nor did it produce a significant decrease in responding on the EtOH or water levers during maintenance responding, it would seem that the effect of JDTic on EtOH-seeking and EtOH-relapse is altering the biological basis of these two phenomena.
The lack of an effect of JDTic, at any dose, on maintenance responding for EtOH is similar to past findings that the KOR antagonist nor-binaltorphimine (nor-BNI) failed to alter operant responding for EtOH in rats and monkeys that were in a non-dependent state (Doyon et al., 2006
; Williams and Woods, 1998
). However, research has shown that nor-BNI does reduce operant responding for EtOH in dependent animals (Walker & Koob, 2008
; Walker et al., 2011
). The selective efficacy of nor-BNI was in contrast to that of naltrexone which, also reduced EtOH intake in non-dependent rats (Walker & Koob, 2008
). Further, microinjections of KOR agents into the nucleus accumbens shell reduced EtOH consumption in rats with prior vapor chamber exposure to EtOH (Nealey et al., 2011
). Thus, it has been hypothesized that the KOR system may not be integral to all processes associated with EtOH reward, but rather undergoes alterations as part of the neuroadaptations underlying EtOH dependence (Walker & Koob, 2008
). It is not known if P rats under the current operant conditions developed EtOH dependence. However, ongoing research has made progress in elucidating the distinct neurochemical system(s) that contribute to EtOH-seeking and/or EtOH relapse. For instance, Rodd et al. (2006)
reported that activation of the metabotropic glutamate (mGlu) 2/3 receptors inhibited the expression of EtOH-seeking as well as EtOH relapse behavior but did not alter maintenance EtOH self-administration (Rodd et al., 2006
). This finding relates directly to the current research as KORs mediate the release of excitatory glutamate in the shell region of the ACB (Hjelmstad and Fields, 2001). On the other hand, exposure to an orexin-1 receptor antagonist selectively decreased EtOH relapse behavior immediately following abstinence but did not affect EtOH-seeking (Dhaher et al., 2010). Thus, the mechanisms underlying EtOH-seeking behavior and EtOH relapse behavior appear to be separable, and support the idea that different mechanisms may mediate relapse and ongoing alcohol drinking. Further research will be needed to tease apart the complex interaction between contributory neurochemical systems.
Alcohol-seeking (i.e., craving) and relapse possess a significant motivational learning component (Heinz et al., 2009
). Several studies have shown that neutral discrete and contextual stimuli that have been previously associated with alcohol, serve to enact behaviors that were associated with alcohol consumption (i.e. operant responding) without alcohol being present or available (for review see: Heinz et al., 2009
). Research attempting to correlate such learned associations with neurological functioning has shown motivational drug learning/associations to be heavily dependent on neural signaling within the extended mesolimbic DA reward pathway (Spanagel & Weiss, 1999
). Within the mesolimbic pathway, there are several secondary neurochemical/receptor systems that have been shown to alter DA release, in turn altering drug related behaviors (for review see: McBride et al., 1999
). For instance, KORs have been found to regulate the release of DA within the ACB. KOR agonists have been found to decrease DA efflux in the ACB (DiChiara & Imperato, 1988; Donzanti et al., 1992
; Spanagel et al., 1992
) whereas a limited amount of research suggests that KOR antagonists, such as nor-BNI, increase basal DA levels in the ACB (Maisonneuve et al., 1994
; Spanagel et al., 1992
). Furthermore, animals repeatedly exposed to EtOH exhibit an enduring increase in DYN tissue levels (Lindholm et al., 2000
) as well as a greater sensitivity to nor-BNI compared to control animals (Lindholm et al., 2007
). With respect to the current data, it is possible that JDTic reduced EtOH-seeking and -relapse by altering the mesolimbic DA system via KOR functioning, which, in turn altered learned EtOH associations/behaviors. However, it is unlikely that mediation of DA signaling by the KOR is solely responsible for the decrease in both EtOH-relapse and -seeking observed in the current study.
The KOR system has been hypothesized to oppose the action of the MOR system in a modulatory manner (Nealy et al., 2011; Walker & Koob, 2008
; Wee & Koob, 2010
). The action of KOR agonists in inhibiting DA release within the ACB is in direct contrast to the action of MOR agonists which increase accumbal DA levels through direct action within the ACB (Di Chiara & Imperato, 1998) as well as the disinhibition of DA neurons in the VTA (Johnson & North, 1992
). This concept of KOR functioning opposing MOR functioning is an important focus in the field of addiction research as it is theorized that the primary reinforcement of virtually every major drug of abuse within the opioid system occurs, either directly or indirectly, through the MOR system (for review see: Contet et al., 2004
). Much like major drugs of abuse, MOR agonists produce reinforcing effects and are readily self-administered directly into the VTA (Devine & Wise, 1994
) and produce conditioned place preferences in rodents (for review see: Shippenberg et al., 1992
). On the other hand, KOR agonists reduce the rewarding properties of intra-cranial self-stimulation (Todtenkopf et al., 2004
) and produce place aversions (Mucha & Herz, 1985
). However, recent research suggests that the KOR system does possess a therapeutic benefit beyond modulating the activity of the MOR system on DA release. Clinical research has found that the combined pharmacotherapy of buprenorphine (partial MOR agonist/KOR antagonist) and naltrexone is more efficacious in patients suffering from opiate addiction than naltrexone alone (Gerra et al., 2006). The combination of naltrexone and buprenorphine significantly decreases the MOR activity while maintaining KOR antagonism (Gerra et al., 2006) further supporting a role for selective KOR antagonism in drug addiction treatment.
The current study showed that JDTic was effective at decreasing EtOH-seeking and EtOH relapse in an animal model for alcoholism. While this effect did not carry over to EtOH maintenance responding, it is believed that JDTic may represent a novel pharmacological compound that will aid in the development of treatments for individuals that are EtOH-dependent and/or suffering from alcoholism. A large majority of individuals suffering from alcoholism, that attempt abstinence, suffer relapse while attempting detoxification (Heinz et al., 2009
). The profile of a KOR antagonist such as JDTic would be efficacious in the population of human alcoholics in many ways. Both stress and depression contribute to EtOH craving as well as relapse rates in human alcoholics (Farren & McElroy, 2010
; Sinha, 2007
). Given the anxiolytic and antidepressive properties of KOR antagonists (Knoll & Carlezon, 2010), such a pharmacological profile would be advantageous for treating comorbid dysphoric states associated with alcohol depencence and perhaps prevent stress-precipitated alcohol relapse. Additionally, since JDTic, as well as other KOR antagonists possess an extended period of action and are in some cases additive in nature, the compliance of individuals taking the drug may be higher due to the fewer number of doses needed. Thus, the development of a pharmacotherapy based on the profile of JDTic/KOR antagonists might possess a greater ability to decrease relapse rates in individuals suffering from alcoholism/alcohol abuse.
>The Kappa opioid receptor mediates some alcohol related behaviors.>We investigated the effect of JDTic on alcohol related behaviors.>JDTic decreased alcohol seeking and relapse but not maintenance responding.>The Kappa opioid receptor mediates alcohol seeking and relapse but not maintenance.>Kappa opioid receptors represent therapeutic targets for the treatment of alcoholism.